title: IP3R1 deficiency in the cerebellum/brainstem causes basal ganglia-independent dystonia by triggering tonic Purkinje cell firings in mice.
abstract: The type 1 inositol 1,4,5- trisphosphate receptor (IP3R1) is a Ca(2+) channel on the endoplasmic reticulum and is a predominant isoform in the brain among the three types of IP3Rs. Mice lacking IP3R1 show seizure-like behavior; however the cellular and neural circuit mechanism by which IP3R1 deletion causes the abnormal movements is unknown. Here, we found that the conditional knockout mice lacking IP3R1 specifically in the cerebellum and brainstem experience dystonia and show that cerebellar Purkinje cell (PC) firing patterns were coupled to specific dystonic movements. Recordings in freely behaving mice revealed epochs of low and high frequency PC complex spikes linked to body extension and rigidity, respectively. Remarkably, dystonic symptoms were independent of the basal ganglia, and could be rescued by inactivation of the cerebellum, inferior olive or in the absence of PCs. These findings implicate IP3R1-dependent PC firing patterns in cerebellum in motor coordination and the expression of dystonia through the olivo-cerebellar pathway.
authors.affiliation: Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute , Wako, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Hisatsune
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyamoto
authors.forename: Moritoshi
authors.initials: M
authors.lastname: Hirono
authors.forename: Naohide
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: Takeyuki
authors.initials: T
authors.lastname: Sugawara
authors.forename: Naoko
authors.initials: N
authors.lastname: Ogawa
authors.forename: Etsuko
authors.initials: E
authors.lastname: Ebisui
authors.forename: Toshio
authors.initials: T
authors.lastname: Ohshima
authors.forename: Masahisa
authors.initials: M
authors.lastname: Yamada
authors.forename: Takao K
authors.initials: TK
authors.lastname: Hensch
authors.forename: Mitsuharu
authors.initials: M
authors.lastname: Hattori
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mikoshiba
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D001479:Basal Ganglia / Q000378:metabolism / Q000503:physiopathology*; D001933:Brain Stem / Q000378:metabolism* / Q000503:physiopathology; D002531:Cerebellum / Q000378:metabolism* / Q000503:physiopathology; D004421:Dystonia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D011689:Purkinje Cells / Q000502:physiology*
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors
keywords: Purkinje cells; SCA15; basal ganglia; cerebellum; complex spikes; dystonia; inferior olive; inositol 1,4,5-trisphosphate